Unilateral hypoglossal nerve stimulation (HNS) is a recent FDA approved treatment of patients with moderate to severe obstructive sleep apnea who cannot or will not use first-line continuous positive pressure therapy for this common and distressing disease. Critical assessment of this technology finds restricted indications, selective and sometimes unpredictable activation of muscles in the tongue which could counter airway opening effects, and safety concerns with the manipulation of a nerve also important in swallowing and speech. An alternative approach would be the stimulation of afferent reflexes to activate a physiologic, brainstem response in upper airway dilator muscles to prevent collapse or maintain airway patency. The novel hypothesis is that in comparison to direct unilateral hypoglossal nerve stimulation (HNS), sciatic nerve stimulation (SNS) (Haxhiu et al. 1984) or a vagally mediated, esophageal transmucosal stimulation (VNS) (Cherniack et al. 1984) will also reverse OSA. We use a rabbit acrylic-injection OSA model for advanced pre-clinical assessments of HNS and the two reflexes (SNS and VNS). Aim 1 includes testing and refinement of approaches acutely under anesthesia. Placement of the HNS, SNS and the VNS electrodes will be optimized. Parameter will first be classically-based settings of amplitude, frequency, and pulse duration. Initial stimulating electrodes will be with hypoglossal nerve wrap electrodes and flat or fine wire electrodes for SNS and VNS. Airflow and manipulation of upstream pressure are measured with a tight fitting nasal muzzle; breathing efforts with chest bands and pulse oximetry examine effort and outcome of apneas/hypopneas, respectively. Cessation of airflow for greater than 2.5 respiratory cycles with persistence of effort or diaphragm EMG will define an obstructive apnea; the absence of airflow without diaphragm EMG activation defines a central apnea. Reduction in airflow and airflow limitation persisting for more than 10 seconds will be define an hypopnea. Fine wire EMG electrodes will be placed into alae nasi, intercostal and diaphragm to record respiratory motor output and its coordination by NS. In Aim 2 for the purposes of studying events during sleep we will implant rabbits with electrodes externalized along with the other insulated recording wires in a head-tether, adding leads for electroencephalography, electrooculography, and nuchal electromyography. This application addresses a need to explore alternatives to OSA in those intolerant of CPAP, using a pre-clinical model where sciences of respiratory control, upper airway physiology and engineering can assess and improve an existing device and explore alternative devices and/or device placement to rationally design a pathway for clinical application.